PB1862: VENETOCLAX AND AZACITIDINE THERAPY IN ACUTE MYELOID LEUKEMIA PATIENTS WITH SEVERE RENAL IMPAIRMENT
Authors: Ryosuke Naka, Tadakazu Kondo, Masashi Nishikubo, Hiroyuki Muranushi, Yasunori Ueda, Tomomi Oka, Fumiya Wada, Junya Kanda, Shohei Yamamoto, Mitsumasa Watanabe, Shinri Okada, Kazunori Imada, Yukiharu Nakabo, Yu Mizutani, Yasuhito Nannya, Seishi Ogawa, Takayuki Ishikawa
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: AML in elderly patients has a dismal prognosis as intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) are not feasible. Recently venetoclax (Ven), combined with hypomethylating agents such as azacitidine (Aza) and decitabine has been shown to be effective in AML in both treatment-naïve and relapsed or refractory settings. This therapy is now widely used as a standard first-line therapy for transplant-ineligible elderly AML patients. Elderly patients often have multiple comorbidities including chronic kidney disease (CKD) at diagnosis or relapse of AML. However, the efficacy and safety of Ven/Aza therapy in patients with severe renal impairment have not been established, as patients with poor renal function were excluded from the pivotal study. Aims: We aim to investigate the efficacy and safety of Ven/Aza therapy in AML patients with severe renal impairment. We also evaluate the optimal dose of each agent and risk of developing TLS (Tumor lysis syndrome). Methods: We retrospectively reviewed the clinical records of 176 AML patients treated with at least one cycle of Ven/Aza in six tertiary medical centers in Japan, from March 2021 to December 2022. We specified 15 patients (8.5%) with severe renal impairment, defined as less than 35 ml/min of creatinine clearance calculated by Cockcroft-Gault equation. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. TLS was assessed based on Cairo-Bishop definition. This study was conducted in accordance with the Declaration of Helsinki. Results: All patients were Japanese with a median age of 83. 12 of 15 cases were de novo AML or MDS/AML. Four patients had an adverse karyotype, and high-risk mutations were confirmed in six out of nine cases whose whole exome sequencing data were available. One patient was on hemodialysis prior to Ven/Aza therapy. Median follow-up time was 180 days (range, 149 to not estimable). Ven/Aza was initiated a median of 5 days (range, 1-26) after diagnosis or confirmed relapse. Ven was ramped up to the maximum dose predefined by antifungal prophylaxis, except for two cases, which were treated with half-dose at most. The dose of Aza was reduced by 20-25% in eight patients. Clinical response after one cycle of Ven/Aza was observed in 12 of 15 patients (80%), with nine achieving complete remission (CR) or CR with incomplete count recovery and three achieving partial remission. As a whole Ven/Aza was continued for a median of two cycles (range, 1-14), and median overall survival was 150 days (range, 113 to not estimable). The most common adverse effect was cytopenia. All except for one patient had grade ≥3 thrombocytopenia. Grade ≥3 anemia was observed in all cases. All but one had grade ≥3 neutropenia, and febrile neutropenia was reported in 12 patients. Two patients died of infections pneumonia after four and one cycle of Ven/Aza, respectively, without evidence of progressive disease of AML. Whereas laboratory TLS was reported in four cases, only one case developed clinical TLS, which was likely associated with sustained hyperbilirubinemia. Serum creatinine levels were decreased except for a few cases showing a transient increase, implying that disease control of AML may be associated with improvement of renal function. Summary/Conclusion: We demonstrate a comparable response rate of Ven/Aza in AML patients with renal insufficiency. Clinical TLS occurred in only one case, and the risk of developing AKI can be managed with appropriate measures. As grade ≥3 cytopenia was reported in all the cases, myelosuppression should be carefully monitored. Keywords: Venetoclax, AML